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CD4+ T Cells from RUPP rat model activate NK cells and cause mitochondrial oxidative stress and hypertension in normal pregnant rats
Author(s) -
Deer Evangeline,
Reeve Kristin E.,
Amaral Lorena M.,
Vaka Venkata Ramana,
Franks Michael,
Fitzgerald Sara,
Herrock Owen,
Ibrahim Tarek,
LaMarca Babbette
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02144
Subject(s) - preeclampsia , oxidative stress , endocrinology , medicine , mitochondrion , blood pressure , chemistry , biology , pregnancy , biochemistry , genetics
Preeclampsia (PE) is new onset hypertension during pregnancy and is associated with elevated inflammatory response such as CD4+ T cells, NK cells, and cytokines. We have previously shown that women with PE exhibit increases in placental mitochondrial (mt) dysfunction and ROS compared to normal pregnant (NP) women. The Reduced Uterine Perfusion Pressure (RUPP) rat model produces many characteristics of PE such as hypertension, increases in CD4+ cells, renal and placental NK cells, and mt dysfunction/ROS. Moreover, we have shown an important role for mt ROS in hypertension in RUPPs. We have previously demonstrated that RUPP CD4+T cells cause hypertension in NP rats, however the role of RUPP CD4+ T cells in stimulating NK cells to cause mitochondrial dysfunction/ROS are unknown. Therefore, we examined the effect of adoptive transfer of RUPP CD4+ T cells to activate NK cells in NP rats and cause mt dysfunction and ROS as mechanisms of hypertension. Splenic CD4+ T cells were isolated from RUPP rats, cultured, and injected into NP rats on gestation day (GD) 13. On GD19, MAP blood and tissue samples were collected. Mt respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. A student’s t‐test was used for statistical analysis. On GD19, MAP increased to 110±2 mmHg (n=12) in RUPP CD4+ T cell recipients compared to control NP rats 101±2 mmHg (n=7, p<0.05). Circulating cytolytic NK cells increased to 3±0.6% in RUPP CD4+ T cell recipients (n=8) compared to NP controls 0.3±0.2% (n=7, p<0.05). Renal state 3 (194.3±62.33 vs 1004±251.9 pmol/sec/mg, p<0.05) and maximal (151.2±75.19 vs 531.5±99.97 pmol/sec/mg, p<0.05) respiration rates, indicative of ATP production and electron transport chain efficacy respectively, were reduced with RUPP CD4+ T cells (n=6) compared to NP (n=4). Renal mtROS increased from 251.5±81.75% in NP controls (n=4) to 416.9±47.68% in RUPP CD4+ T cell recipients (n=9, p<0.05). Collectively, the data indicate that the adoptive transfer of RUPP CD4+ T cells stimulates cytolytic NK cells and renal mitochondrial dysfunction/ROS during pregnancy as important mechanisms of hypertension in the pathophysiology of preeclampsia. Support or Funding Information NIH Grants: RO1HD067541‐06 and P20GM121334; T32HL105324